The early detection of cancer has been one of the primary goals of modern imaging technology, since the identification of a suspected tumor in a localized stage significantly improves the chances for successful treatment and elimination of the cancerous tissue. A large number of imaging strategies have therefore been designed, using a variety of techniques and modalities, to aid the physician in making an accurate diagnosis as early as possible.
Approximately 130,000 new cases of colorectal cancer are diagnosed each year in the United States. Thus colorectal cancer is the fourth most common cancer, accounting for 60,000 deaths per year (Cancer Facts and Figures. American Cancer Society 2001). Treatment depends primarily on the cancer stage, but may include surgery, radiation, chemotherapy, and/or radiofrequency or cryo-ablation. In routine follow-ups for colorectal cancer patients, however, determination of carcinoembryonic antigen (CEA), a colorectal tumor marker, and repeat colonoscopies (O'Dwyer P J, et al., Follow-up of stage B and C colorectal cancer in the United States and France. Seminars in Oncology 2001; 28: Suppl-9) fail to detect recurrent disease in over 50% of patients. See Wichmann M W, et al., The Colorectal Cancer Study Group; Carcinoembryonic antigen for the detection of recurrent disease following curative resection of colorectal cancer. Anticancer Research 2000; 20:4953-4955. Therefore, there is a need for development of additional methods for detection of recurrent disease.
Virtual colonoscopy, a non invasive scanning procedure performed by Computed tomography scanning in humans has been reported to be more accurate than traditional colonoscopy. (Pickhardt P J. et al., Computed tomographic virtual colonoscopy to screen for colorectal neoplasia in asymptomatic adults. New England Journal of Medicine. 349(23):2191-200, 2003 Dec. 4. Performed on a traditional multidetector helical CT scanner, virtual colonoscopy allows one to noninvasively scan the intestinal lumen anatomically for tumors but cannot characterize space occupying lesions as either polyps (adenomas) or adenocarcinomas (malignant). Determination of tumor type dramatically effects treatment planning and outcome for these patients.
In addition, functional information from CT scans is difficult to obtain during treatment and diagnosis using RF ablation and CT scanning. With contrast-enhanced helical CT, tumor vascularity may be assessed to some degree, but there is no way of accurately determining if viable tumor cells remain within the RF-ablated lesion. In addition, the thermal lesions created by RF normally have a rim of inflammation surrounding them on post procedure CT scans for up to 6 months post-ablation. PET scanning has been used to follow post-ablation patients, but the rim of inflammation surrounding RF thermal lesions normally displays increased uptake, even in the absence of a viable tumor. This decreases the sensitivity and specificity for early detection of recurrent tumor. Accordingly agents that are selective for and retained indefinitely by malignant tumor cells are preferable unlike fluorodeoxyglucose (FDG) which is not selective for tumor cells and is localized to infectious sites and hyperplasias (such as Barrett's Esophagus). Moreover compounds containing 124I, which has a 4 day physical half life and can thus be shipped anywhere in the world, are preferable to FDG, which has a 110 minute half life and therefore may only be have limited distribution within 200 miles of the production site.
Compounds that undergo prolonged retention (and are not metabolized) are preferable since it is more likely that they may have significant therapeutic potential when mated with an appropriate radioisotope like 125I, 131I or 211At. Also, compounds which can be labeled with a variety of iodine isotopes and have expanded versatility (diagnosis and therapy as well as a tool for experimental animal studies) are preferable to FDG, which is limited to 18F for PET scanning or potentially 19F (stable) for magnetic resonance imaging, albeit at very low sensitivity levels. Additional compounds disclosed to be useful for PET include 124I- or 131I-labeled 2′-fluoro-2′-deoxy-1-β-D-arabinofuranosyl-5-iodouracil (FIAU), 18F-labeled 9-[4-fluoro-3-(hydroxymethyl)butyl]guanine (FHBG), and 18F-labeled 9-[3-fluoro-1-hydroxy-2-propoxymethyl]guanine (FHPG). Regardless of its tumor targeting ability, 18F-FDG, due to its rapid metabolism in tumor cells, does not have potential for therapy. Therefore, other compounds are needed to investigate post therapeutic local recurrences.
Moreover, even where chemotherapy is the mode of treatment, improved monitoring of the response to chemotherapy is essential. Therefore, development of an early prognostic indicator to study response to chemotherapy to allow physicians to quickly discontinue use of ineffective chemotherapeutic regimens without exposing patients to the toxicity of prolonged treatments is desirable. Where External Beam Radiation Therapy is an alternate treatment for patients with tumors of similar histology, tumors may have dramatically different responses to curative-intent external radiation therapy (XRT). Some patients with rectal cancer treated with pre-operative radiation will have a complete response, while others with similar histology (at the light microscopy level) will have a poor response to treatment and will recur. Response to radiation is a predictive factor for ultimate tumor control and survival for many cancers, including many gastrointestinal cancers, lung cancer, head and neck cancer, and gynecologic cancers. Most response characterization methods, while very predictive of response, are performed after completion of treatment. While some intra-treatment clinical assessments are useful in adjusting treatment (Mayr, N. A., et al. Method and timing of tumor volume measurement for outcome prediction in cervical cancer using magnetic resonance imaging. International Journal of Radiation Oncology, Biology, Physics 2002; 52; 1:14-22), in most cases there is no accurate method of predicting tumor response during actual treatment. Such a test, especially one applicable to a broad range of tumor sites and histologies, would be very useful and desirable. Other treatment and diagnostic methods include molecular assays that have been proposed to predict response to therapy, and recent efforts include use of DNA microarrays to identify genetic changes that correlate with response or lack of response to treatment. These are investigational and none are in routine clinical use.
Yet other methods of diagnosis and treatment include use of imaging modalities to predict response during XRT treatment. Intra-treatment PET scans using FDG are under active investigation, wherein the isotope uptake in the primary tumor midway through radiation therapy is compared to the pre-treatment uptake. Several retrospective studies suggest patients with continued strong uptake during treatment have poorer tumor control outcomes than patients whose tumors are less FDG-avid during treatment (Greven, K., et al., Can positron emission tomography distinguish tumor recurrence from irradiation sequelae in patients treated for larynx cancer? Cancer Journal Scientifica American 1997; 3: 353-357). However, more effective screening, diagnostic and treatment agents and methods for various cancers are extremely desirable.
Unfortunately, conventional imaging techniques such as computerized tomography (CT) and MRI (magnetic resonance imaging) are limited in their ability to afford a conclusive diagnosis of a suspected lesion, since they are only capable of observing differences in the density or morphology of tissues. A more invasive and costly biopsy procedure is often necessary to provide a definitive diagnosis. In contrast, nuclear medicine techniques such as positron emission tomography (PET) and single photon emission tomography (SPECT) can provide functional or biochemical information about a particular organ or area of interest. However, the success of these nuclear imaging techniques depends in large part on the selective uptake and detection of appropriate radiopharmaceuticals. Selective uptake, in turn, depends upon the development of radiopharmaceuticals with a high degree of specificity for the target tissue. Unfortunately, the tumor-localizing agents developed thus far for oncological applications have had only limited application.
For example, one of these prior art compounds, 67Ga gallium citrate, was originally identified for its ability to accumulate in tumor tissue. Unfortunately, 67Ga gallium citrate is taken up by a variety of other non-tumor lesions as well, including inflammatory lesions, and unacceptable amounts of radioactivity can also accumulate in liver and spleen. The rapid buildup of a radiopharmaceutical in these organs can seriously interfere with the imaging of nearby lesions and also reduces the dosage that can safely be given to a patient.
An alternative approach has been to develop radiolabeled monoclonal antibodies (Mabs) directed to tumor-specific antigens. However, these monoclonal antibodies are specific only to the particular tumor tissue for which they have been produced, and therefore will not localize generally in neoplastic tissue. Moreover, the use of Mabs for diagnostic imaging has lead to additional problems, including varying degrees of antigen expression, low tumor uptake, non-specific binding and adverse immunogenic reactions and generally high liver localization.
In an attempt to address these problems, the present inventors have recently identified and developed a series of novel compounds demonstrating useful tumor selectivity. See, e.g., U.S. Pat. Nos. 4,925,649; 4,965,391; 5,087,721; 5,347,030; 6,255,519 and 6,417,384; all of which are herein incorporated by reference. It is believed that these radioiodinated phospholipid ether analogs take advantage of a unique biochemical characteristic of malignant tumor cells; i.e. the inability to metabolize phospholipid ether analogs relative to corresponding normal tissues. Although the precise mechanism of action is not fully understood, the prevailing hypothesis is that the phospholipid ether analogs become entrapped in malignant tumor cell membranes due to an apparent lack of appropriate metabolic enzyme. Accordingly, these compounds localize in tumor cells and become biochemically locked in place for diagnostic and/or therapeutic applications. Currently available oncologic PET agents such as 18F-FDG, localize in benign lesions and inflammatory sites as well as in tumors, and are thus not good indicators of malignancy.
Accordingly, there remains a significant need in the art for radiopharmaceuticals which exhibit a rapid clearance from non-target tissues as well as an extended half-life in the plasma, while still retaining its specificity and avidity for neoplastic tissue. Such an agent should not only assist in the non-invasive imaging and characterization of primary tumors and metastases, regardless of their location in the body, but should also serve as a carrier for a cytotoxic agent for site-specific eradication of malignant tumor tissue, especially as it relates to the most frequently diagnosed forms of cancer. It is further desirable that radiopharmaceuticals are selective for malignant tumors and not precancerous tissues including adenomas and hyperplasia.
Therefore, a readily available radiopharmaceutical that could accurately identify and potentially treat early metastatic disease in the patients with colorectal cancer would have an important impact on patient care, in terms of both staging and response to therapy. There remains a need for an accurate functional imaging technique based upon a tumor-specific function that can non-invasively screen the whole body using relatively inexpensive and widely available imaging devices.